Event-Related Potentials and Cognitive Function in Alcoholism.

Subtle cognitive deficits can be studied using event-related potentials (ERP), brain waves elicited in response to sensory stimuli. ERP studies suggest that certain memory processes are impaired in alcoholics; therefore, each incoming stimulus must be evaluated anew. Some ERP anomalies occur in nonalcoholic subjects from alcoholic families, indicating that these anomalies may antecede the development of alcoholism.

C ognitive impairment in alco holics 1 ranges from severe mem ory disorders and dementia to subtle impairment of the ability to process and interpret sensory informa tion. A majority of alcoholics may exhibit subtle cognitive impairment. For many years, these milder deficits were not well understood because the sensitive tech niques required for their detection were unavailable.
Today, subtle cognitive deficits can be studied using eventrelated potentials (ERP), a special application of the elec troencephalogram (EEG). Traditional EEG techniques use electrodes placed in standard positions on the scalp to measure the spontaneous electrical activity of the brain. Characteristic EEG patterns have been correlated with different mental and 1 Throughout this article, terms such as "alcoholism," "heavy drinking," and "alcohol abuse" are used. These terms are not used consistently in the alco holism literature; therefore, the wording in each case is based on the terms used in the reference cited. behavioral states. In contrast, ERP's are elicited in response to sensory stimuli, such as sights or sounds. Brain electrical responses can be measured within a frac tion of the second that follows exposure to a stimulus, providing an immediate record of brain activity associated with information processing.

HOW ERP'S ARE OBTAINED
The brain can generate ERP's in response to stimuli in any sensory system, or chan nel. In most ERP experiments, subjects are exposed to stimuli in the visual or auditory channels (or both). Visual stim uli, such as shapes or letters, can be pre sented on a computer screen; auditory stimuli, such as tones or clicks, can be presented through headphones. The sub ject may be asked to attend to some stim uli while ignoring others. Generally the subject is asked to make a behavioral response to a certain stimulus. For exam ple, he or she may be asked to press a button whenever the stimulus is detected. Stimuli that require a response are called targets. In some tasks, the subject must attend or respond to a specific stimulus in one sensory channel while ignoring all stimuli in another sensory channel; the sensory channel containing the target stimulus is called the relevant channel.
Scalp electrodes record the subject's brain electrical activity during the task. The electrical signals are processed elec tronically and displayed as undulating lines, each line forming a series of peaks (positive waves) and valleys (negative waves). Waves, or components, 2 are named according to their polarity-posi tive (P) or negative (N)-and their latency. Latency is the interval, in thousandths of a second (milliseconds [msec]) between the occurrence of a stimulus and the peak of the wave.
Early ERP components (those with latency less than 100 msec) are automatic responses to physical characteristics of the stimulus. In contrast, later components reflect the subject's processing of the stimulus and are influenced by the psychological circumstances under which the stimulus is presented.

WHAT ERP'S INDICATE ABOUT COGNITIVE PROCESSES
Various mental operations are involved in responding to a target stimulus. For exam ple, the subject must focus attention on the relevant sensory channel, ignore irrelevant stimuli, distinguish among similar stimuli, and then recognize the target stimulus by matching it to a template stored in the mem ory. These operations are correlated with electrical activity in groups of nerve cells from the sense organs themselves (i.e., eyes, ears) to the highest centers of infor mation processing in the brain. Researchers have identified certain ERP components that appear to reflect these operations. ERP components between experimental and control subjects are compared in terms of changes in latency and differences in wave height (i.e., amplitude).

Selective Attention: N1 and Nd
N1 (or N100) is a negative wave occurring approximately 100 msec after a stimulus. N1 consists of two components that may overlap in time-an earlier automatic com ponent followed by an attentionrelated component. The automatic component of N1 is the same in both the relevant and ir relevant channels. In normal subjects, N1 has a greater amplitude when elicited by stimuli in a relevant sensory channel com pared with the N1 elicited by stimuli in an irrelevant channel. Therefore, to examine the attentional process, the amplitude of the N1 from the relevant channel is sub tracted from that of the irrelevant channel, yielding an Nd ( subject's allocation of attentional resour ces to the appropriate channel. In one experiment (Porjesz and Begleiter 1979), alcoholics who had been abstinent for an average of 1 month were presented with sequences of random single flashes and single clicks interspersed with more rarely occurring double flashes and dou ble clicks. For each sequence, subjects were instructed to count either the double flashes or double clicks or else to ignore all stimuli in the sequence. ERP's were re corded only to the frequent single flashes, which were either in the relevant channel (when double flashes were counted) or the irrelevant channel (when double clicks were counted). Alcoholics maintained a low ampli tude of N1 regardless of channel relevance, thereby exhibiting small or absent Nd components. These results suggest that alcoholics do not differentiate between relevant and irrelevant sensory channels.
In a similar experiment using visual stimuli, Patterson and colleagues (1987) found diminished visual Nd amplitudes in abstinent alcoholics. N1 amplitudes were reduced to both the frequent nontargets and rare targets in the relevant channel. These results suggest that alcoholics may have greater difficulty with visual, compared with auditory, selectiveattention tasks.
At least two kinds of P3 have been identified: Unattended oddball stimuli elicit P3a's, and attended oddball stimuli in a repetitive background elicit P3b's. Most studies have dealt with the P3b component (for review, see Regan 1989).
Porjesz and colleagues (1980) used a visual task involving geometric shapes to study P3 in alcoholics abstinent an aver age of 2 months. The shapes included squares, triangles, and rarely occurring irregular forms interspersed in random order. Subjects were instructed to press a button in response to the rarely occurring target stimulus; in consecutive test se quences, squares alternated with triangles as rare targets. P3's were recorded in response to the triangle, both when it was the target and when it was a nontarget.
Nonalcoholic control subjects exhibit ed larger late P3 components to target stimuli compared with nontarget stimuli (figure 1a). Alcoholics, however, mani fested reduced or absent P3 components that differed little in amplitude, whether the stimulus was a target or a nontarget (figure 1b) (for review, see Porjesz and Begleiter 1983, 1985.

Difficulty of Discrimination.
Many ERP studies have demonstrated that the more deviant a rare stimulus is from the back ground (i.e., the more easily it can be discriminated), the larger the P3 ampli tude (for review, see Regan 1989). This effect was examined in a visual oddball task using line stimuli . P3 components were obtained in response to two target lines-one that was easy to discriminate (90 degrees from a vertical nontarget line), and one that was more difficult to discriminate (only 3 degrees from the vertical nontarget).
As predicted, nonalcoholics exhibited significantly larger P3 amplitudes to the 90degree target than to the 3degree target. Alcoholic subjects did not exhibit significant differences in P3 amplitude between easy and difficult targets or between targets and nontargets. This indicates that alcoholic subjects find the discrimination task more difficult and are more uncertain of their responses. In addi tion, alcoholic subjects tend to stress speed over accuracy in some cognitive tasks. In the above study, alcoholics exhibited faster reaction times 3 and made more errors than nonalcoholic subjects. This suggests that alcoholics may respond to stimuli without fully evaluating them (for review, see . Results from P3 auditory tasks are not as consistent as those from visual P3 tasks, although several studies have reported decreased P3 amplitudes in alcoholics relative to nonalcoholics in auditory target selection and oddball tasks (Patterson et al. 1987;Porjesz et al. 1988;Pfefferbaum et al. 1991;Cohen et al. in press).

Stimulus Evaluation Time.
Alcoholics exhibit delayed P3 latencies to attended auditory targets but not to attended visual 3 Reaction time is less precise than ERP latency as a measure of the speed of information processing, because the reaction time depends on a combination of several cognitive processes followed by motor response.
targets. Compared with nonalcoholics, alcoholics also exhibited reaction time delays in auditory but not visual oddball tasks (Pfefferbaum et al. 1991). Auditory oddball tasks in general appear to be easier than visual tasks. Therefore, the factor influencing P3 latency delays in these studies is probably not the sensory channel involved but rather overall ease of discrimination.
In the visual line discrimination task, nonalcoholic subjects manifested significantly earlier P3 latencies to easy discriminations compared with difficult discriminations. In alcoholics, P3 latency was delayed for the easy targets, such that P3 latency was comparable for both easy and difficult targets. These results suggest that alcoholics found both discriminations difficult and adopted an undifferentiated mode of responding regardless of task requirements (for review, see . Although most attention has been focused on P3b tasks in which subjects attend to target selection, a small number of studies have examined P3a. In two P3a studies using auditory oddball tasks, alcoholics manifested lower P3a ampli-tudes than did nonalcoholics to rare unattended stimuli (Pfefferbaum et al. 1991;Realmuto et al. 1993).

Evaluating the Stimulus: N2
The relationship between difficulty of discrimination and speed of stimulus evaluation can be examined in visual tasks using N2, a negative component that occurs at approximately 200 msecs after a stimulus. One study ) used the line target discrimination task described above, with frequently occurring vertical nontargets interspersed with both easy and difficult rare targets. Subjects were instructed to press a button as quickly as possible to all nonvertical stimuli.
In nonalcoholic subjects, the latency of N2 reflected the difficulty of discrimination, being significantly delayed for the difficult compared with the easy discriminations. In contrast, alcoholics manifested similar N2 latencies regardless of discrimination difficulty. Moreover, the N2 latency in alcoholics occurred significantly later than in nonalcoholics for both the easy and difficult discriminations, suggesting that alcoholics find both discriminations more difficult and need more time for stimulus evaluation. Other researchers have reported similar delays in N2 latency in alcoholics in visual oddball tasks (Glenn et al. 1993).
On the basis of both the N2 and P3 ERP studies, it appears that alcoholics have less efficient match-mismatch memory processes than do nonalcoholics and hence have more difficulty evaluating the potential significance of stimuli.

Semantic Memory: N400
N400 is a negative component occurring approximately 400 to 600 msec after a stimulus. It is most typically recorded during the presentation of a sequence of contextually related words in which one of the words is semantically incongruent. For example, the sentence "I take my coffee with cream and socks" would elicit a large N400 to the word "socks," whereas the sentence "I take my coffee with cream and sugar" would not elicit an N400 to the word "sugar." The more incongruous the word, the larger the N400 (for review, see Kutas and Van Petten 1988).
Another way to obtain an N400 is by means of semantic priming of single words. A word is responded to more quickly and accurately if it is preceded by the same or related words (primed) than if it follows unrelated words. In the example "table-chair," "chair" is said to be primed by "table." Semantic priming can be measured either with reaction time or the N400 ERP. In normal subjects, unprimed words elicit larger N400's than primed words; primed words elicit small or absent N400's.
In a recent study examining the N400 component in alcoholics, subjects were required to indicate as rapidly as possible whether a given sequence of letters formed a word. Words preceded by their antonyms (e.g., hot-cold) were more quickly recognized as words than were those preceded by unrelated words or nonsense syllables. In nonalcoholic subjects, the N400 component was elicited by the unprimed words but not by the primed words. However, alcoholics exhibited N400's to primed and unprimed words alike . This study marks the first time semantic memory deficits have been demonstrated in alcoholics using measures of brain electrical response.

Memory Potentials
Priming deficits are not limited to seman tic stimuli. The visual memory potential (VMP), occurring about 240 msec after a stimulus, is elicited in visual matching tasks using pictures of faces or objects, or shapes. In nonalcoholics, primed or match ing stimuli elicit smaller and faster VMP's than do nonmatching stimuli. In contrast, alcoholics manifest similar VMP's to both matching and nonmatching stimuli in terms of both amplitude and latency. These re sults suggest that alcoholics do not use available information about the physical features of stimuli to facilitate or prime their responses to identical stimuli .

Memory Dysfunction and Disinhibition
Taken together, the research described above suggests that alcoholics manifest two types of memory dysfunction: The low P3 amplitude suggests that the tem plate matching processes are impaired, and the delay in N2 latency suggests that the template itself may be lost or absent. Furthermore, these findings suggest a lack of inhibition in alcoholics as reflected by their apparent inability to withhold re sponding until the certainty of accuracy or correctness has been established.
Evidence from monkey studies indi cates there is less nerve cell electrical activity (firing) in response to repeated or primed stimuli, suggesting selective inhibi tion of masses of nerve cells (Miller et al. 1991). This differential inhibition facili tates the efficient processing of a familiar stimulus. This process seems to be im paired in alcoholics, such that each incom ing stimulus must be evaluated anew.

RECOVERY OF COGNITIVE FUNCTIONING WITH ABSTINENCE
Research indicates that alcoholics continue to manifest low P3 amplitudes after 3 to 10 years of abstinence. In contrast, abnor malities in certain early sensory compo nents known as brainstem auditory evoked potentials (BAER) recover com pletely. In addition, a study conducted in Spain indicates that while P3 does not recover following 4 months of abstinence, N2 latency recovers completely (Grau et al. 1992). These observations suggest that anomalies of some components (e.g., BAER, N2) may be consequences of heavy drinking, whereas anomalies that do not recover with prolonged abstinence (e.g., P3) may antecede the development of alcoholism.
In this regard, it is noteworthy that N2 latency may predict whether a recovering alcoholic will resume drinking. Glenn and colleagues (1993) evaluated alcoholics in a visual oddball task after approximately 1 month of abstinence and again after 1 year. Subjects who resumed drinking within the year manifested longer N2 latencies at initial testing than did those who remained abstinent. Results were not affected by a subject's family history of alcoholism. Thus, whereas P3 amplitude may predict susceptibility to developing alcoholism (see below), N2 latency may predict susceptibility to relapse (for re view, see .

FAMILY HISTORY AND RISK OF ALCOHOLISM
The cognitive and other brain abnormali ties observed in alcoholics have tradition ally been attributed to the toxic effects of alcohol, nutritional deficits, or an interaction of toxic and nutritional factors. Increasing evidence suggests that at least some ERP aberrations may antecede the develop ment of alcoholism.
Population genetics studies suggest that genetic factors predispose sons of alcoholic fathers to alcoholism (for review, see Hesselbrock in press). Evidence indicates that characteristics of both the EEG and ERP are themselves genetically deter mined. For example, the heritability of P3 amplitude recently has been reported to be high for both visual  and auditory P3 (O'Connor et al. 1994).
The first study to indicate that P3 am plitude is significantly reduced in boys at risk for alcoholism was undertaken 10 years ago (Begleiter et al. 1984). Subjects at risk were sons of alcoholic fathers; age matched control subjects had no family history of alcohol problems. All subjects were between 7 and 13 years of age and did not drink alcohol. The task involved discrimination of rarely occurring easy and difficult visual stimuli representing greatly simplified views of a head from above. Further research has replicated these find ings for both postpubescent (O'Connor et al. 1986) and prepubescent (Hill and Steinhauer 1993a) sons of alcoholics. Similar results have been obtained with other visual tasks (Whipple et al. 1988(Whipple et al. , 1991Noble 1990;Berman et al. 1993;Porjesz and Begleiter 1990) as well as with an auditory task .
A recent metaanalysis 4 (Polich et al. 1994) reported a consensus that P3 ampli tude is decreased in subjects at risk for alcoholism. This decrease is most likely to be observed in prepubescent males using difficult visual tasks. Results in older offspring are more variable, particu larly with easy auditory tasks.
A study by Berman and colleagues (1993) suggests that P3 amplitude in prepubescent boys may predict later alcohol or other drug (AOD) abuse in adolescence. Four years after initial ERP testing, adolescents were administered a questionnaire dealing with AOD use. Subjects exhibiting the lowest P3 ampli tudes at initial testing had the highest AOD use scores in adolescence. These findings provide strong evidence that P3 amplitude in prepubescent boys may serve as a vulnerability marker for the development of later AOD use disorders. 5 The studies discussed above have used males as subjects almost exclusively. Results of studies in females have been inconsistent. A recent nationwide study with very large sample sizes found lower P3 amplitudes in female alcoholics and their firstdegree relatives, 6 although not to the same extent as in males . In both men and women, short er P3 latencies in nonalcoholic siblings suggest a protective effect against the development of alcoholism (Hill and Steinhauer 1993a,b).

SUMMARY AND CONCLUSIONS
Research indicates that various ERP com ponents are aberrant in alcoholics under certain conditions. These aberrations are associated with impaired ability to match a stimulus with the memory template of a familiar stimulus. On a more basic level, the alcoholic may have difficulty retrieving the template; it remains to be determined whether the template has not been laid down or is lost.
Some aberrant components are obtained in subjects at risk for alcoholism, indicating that these ERP anomalies may antecede the development of alcoholism. The reduced P3 amplitude in highrisk subjects may serve as a marker for susceptibility to the development of alcoholism. However, a reduced P3 amplitude alone may not nec essarily be specific for alcoholism. A cluster of ERP measures (P3, N400, VMP) suggests disinhibition of nerve cell firing and together may represent a more specific marker for a predisposition for alcoholism than reduced P3's alone.
Not all individuals manifesting these potential markers will necessarily develop alcohol problems or the disease of alco holism. Longitudinal family studies are underway as part of the Consortium on the Genetics of Alcoholism (COGA) project to examine alcoholic and nonalco holic family members over time. It is hoped that this approach will elucidate the link between measures of risk and the development of alcoholism. As these ERP measures are genetically determined, the data imply that a predisposition or vulner ability to alcoholism is inherited. The role of the geneenvironment interaction is not to be minimized in determining whether an individual manifesting this predisposi tion goes on to abuse alcohol. ■